• Fetal Origins Literature Review

    Nambi Ndugga is a Policy Analyst with Boston University’s School of Public Health. She tweets at @joerianatalie.

    What follows is a summary of articles that look at the effects on in-utero exposure to a variety of stressors on future health outcomes. First, some definitions:

    The fetal origins hypothesis (FOH) states that disruptions to fetal nutrition have significant effects on future health outcomes. David Barker, who is credited with the development of the theory, determined that nutritional mismatch between the intrauterine and postnatal environments could result in adverse health outcomes in later life. Barker’s original work looked at the relationship between mid to late gestation undernutrition and programmed cardiovascular and metabolic illness in later life. Current research expands on FOH to include other prenatal pathways and postnatal outcomes. These have informed the development of the Developmental Origins of Health and Disease hypothesis (DOHAD).

    DOHAD was formalized in the early 2000s through the formation of the International Society for Developmental Origins of Health and Disease. The hypothesis states that the period from conception to early childhood is critical to an individual’s immediate and future health. DOHAD expands on FOH by first recognizing the limits of nutrition as a marker of prenatal pathways to postnatal outcomes. It then includes other physical, environmental, and psychological stressors on the fetus and their effects on future health outcomes. Currently, both DOHAD and FOH are interchangeably used to describe the effects of prenatal growth and development on future health outcomes. For the remainder of this post, I will use FOH or simply “fetal origins.”

    The Brenner hypothesis adheres to the DOHAD hypothesis but has a narrower scope. It posits that individuals with a reduced nephron number (number of nephrons per kidney) have an increased risk of future non-communicable disease. Reduced nephron numbers are associated with intrauterine growth retardation that results in low birth weight and premature birth, both major indicators of future non-communicable diseases, including chronic kidney disease.

    Studies based on the 1918 Influenza Pandemic

    The 1918 Influenza Pandemic served as a natural experiment to study the fetal origins hypothesis. The pandemic arrived suddenly in October 1918 and lasted until January 1919 and affected 1/3 of pregnant women and their fetuses. Using US census data, researchers found that certain outcomes (educational, professional, etc.) followed similar patterns for the affected population throughout their lifespans.

    Almond and Mazumder (2005) used data from the Survey of Income and Program Participation from 1984 to 1996, to look at health outcomes of cohorts who were in utero during the 1918 Pandemic. They found that cohorts in utero during the Pandemic had more adverse health outcomes throughout the lifespan compared to the cohorts born a few months earlier or later. Specifically, the research found that later life risks of cancer, heart problems, kidney problems, hypertension, and stomach problems have a statistically significant association with those who were in-utero during the height of the Pandemic. They also found that the 1919 cohort experienced a significant increase in incidences of functional limitations, including trouble hearing (19%), speaking (35%), lifting (13%), and walking (17%).

    Mazumder et al. (2010) looked at the effects of maternal exposure to infections during pregnancy and its effects on fetal programming (when the fetal environment predisposes the fetus to postnatal disease). They found that cohorts that were in-utero during the 1918 Influenza Pandemic were associated with a greater than 20% excess incidence of adult on-set cardiovascular disease, specifically ischemic heart disease. They also found that those born during the Pandemic had excess incidences of diabetes, later in life. A potential study limitation is that their analyses were based on self-reported data. However, other studies have corroborated these findings with medical records. The researchers identified potential pathways between prenatal infection exposure and adult health outcomes. It is possible that prenatal exposure to influenza increases the risk of low birth weight, a known risk factor of later heart disease and diabetes.

    Fletcher (2014) used the National Longitudinal Mortality Study to look at the mortality effects of those who were in utero during the 1918 Influenza Pandemic. While the study authors did find some links between in-utero exposure to influenza and educational attainment, but they did not find statistically significant evidence linking in-utero exposure to influenza and later mortality outcomes.

    A study based on prenatal radiation exposure

    The CDC found that prenatal exposure to radiation can increase an individual’s risk of cancer in later life. The level of risk is dependent on the amount of radiation the fetus is exposed to and its gestational age.

    Studies based on prenatal heavy metal exposure

    Bailey and Fry (2014) found associations with prenatal and early-life exposure to inorganic arsenic and later in life health outcomes including, cancer, intellectual function, and other non-communicable diseases. Similar to the radiation exposure, the health outcomes are dependent on the level or extent of exposure and the gestational age of the fetus.

    Dauphine et al. (2010) conducted a pilot study in Chile looking at the effects of in-utero and childhood exposure of arsenic in drinking water on adult lung function. They drew comparisons between two cities, one where the inhabitants primarily, if not exclusively, used the arsenic-contaminated municipal water supply and another where inhabitants had minimal to no exposure. The researchers found that a link between in-utero and childhood exposure to arsenic in drinking water and long-term lung function deficits and shortness of breath in adulthood. The effects measured are equivalent to those found in those who smoke throughout their adult lives.

    Studies based on fasting

    Xi Chen (2014) used Ramadan fasting and festival activities as natural experiments to determine the effect of under-nutrition on prenatal health and subsequent effects on later health. In-utero exposure to maternal fasting can lead to developmental adaptations that are good for the survival of the fetus in the short term, but will result in stunted fetus growth and may increase the risk of non-communicable diseases in later life. They found that exposure to maternal fasting retards the development of a specific placental enzyme needed to convert the stress hormone cortisol to its inactive form cortisone, exposing the fetus to excess stress hormone, a known in-utero influence of adult health. The excess exposure may lead to the reprogramming of Hypothalamic Pituitary Adrenal axis which is linked to type 2 Diabetes, high blood pressure, and cognitive impairment.

    Ewijk et al. (2013) looked at maternal nutrition during Ramadan to determine if intermittent fasting had lasting effects on fetal physiology. They looked at birth information, and height and weight measurements of 14,120 people (12,900 Muslims and 1220 non-Muslims).  They found that Muslim individuals who were conceived or were in mid to late gestation during Ramadan were both thinner and shorter than those who were not Muslim. They found that the average adult BMI of Muslims who were exposed to Ramadan in-utero was 0.32 units lower than those who weren’t. They also found that those who were exposed to Ramadan during gestation were 0.20 cm shorter than those who weren’t exposed, however this finding was not statistically significant.

    Almond and Mazumder (2008) used Ramadan as a natural experiment in fasting and fetal health. They looked at census data from several countries (US, Iraq, Uganda) to look at birth date, location, and disability status. They found strong associations between exposure to Ramadan and the increased risk of disability, especially intellectual disabilities. In Uganda, they found that Muslims born nine months after Ramadan (month-one exposure to Ramadan) saw a 22% increase on the mean disability rate (3.8%). The Iraqi census demonstrated similar results with exposure to Ramadan in the first month of pregnancy resulting in a 23% increase on the rate of disability relative to the mean (1.5%). In US they found a 18% increase on the rate of disability relative to the mean (6.07%).

    Studies based on environmental maternal stress, including war, natural disasters, famine

    Akresh, Caruso, Thirumurthy (2014) looked at the impact of armed conflict on subsequent health outcomes. The researchers compared children near the conflict sites compared to those further away. They found that children who were exposed to war in-utero experienced a subsequent 0.306 reduction in their age-adjusted height measurements, those who were exposed in early childhood (9 months after birth) experiences a 0.423 reduction in age-adjusted heights. The effects were higher in children from the losing country, in this case, Eritrea, compared to the winning country, Ethiopia. The impact increased if the intensity of the conflict was greater. The researchers used the concentration of war induced displacement, geographic proximity to fighting, and the length of time exposed to the conflict as proxies for conflict intensity.

    St. Clair et al. (2005) studied the effects of intrauterine nutritional deficiency on the development of adult schizophrenia using the 1959-1961 famine in China as a natural experiment. They found that cohorts exposed to the famine had an increased risk of adult schizophrenia, those born before the famine had a 0.84% risk (1959), those born during the famine had a 2.15% risk (1960), and those born after the famine had a 1.81% risk (1961). Their findings replicated those of studies that looked at the effects of in-utero exposure to the 1944-1945 Dutch Hunger Winter which found that the birth cohort conceived in the height of the famine had a 2-fold increase in risk of Schizophrenia.

    A study based on psychological stress

    Persson and Slater (2016) studied how in-utero exposure to maternal stress from family ruptures affects mental health in later life. They found that exposure to severe psychological stress in utero, such as the death of a close family member has causal impacts on the development of future psychological conditions. They found that in-utero exposure to the death of a mother’s close relative has a large effect on the consumption of prescription drugs for mental health conditions. In children they found a 25% increase in the likelihood of purchasing ADHD medications, and a 24% increase in the average daily dose of ADHD medication. In adults they found an 8% increase in the likelihood of consuming prescription drugs for anxiety and depression, and a 19% and 12% increase in the average daily doses of these drugs.

    Conclusion

    A substantial body of research demonstrates that in-utero exposures to stressors influence future health outcomes. Given the prevalence of non-communicable diseases worldwide, this may provide policy makers and healthcare practitioners additional approaches to improve health.

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